PROJECT SUMMARY/ABSTRACT Oral cavity squamous cell carcinoma (OCSCC) is an aggressive and deadly disease. While tobacco and alcohol abuse are the risk factors of carcinogenesis in traditional high-risk OCSCC patients, there is a subset of young patients, even in the absence of these risk factors, who develop sporadic OCSCC. The cause of OCSCC in young patients remains unknown and despite their young age and lack of risk factors have poor survival. Based on our preliminary data, there appears to be demographic, etiologic, and mutational burden differences between younger, low-risk (?40 years, non-smokers and non-drinkers) and traditional, high-risk (>50 years, >20 pack-years of tobacco use and high alcohol use) patients. We are seeking to utilize genomic and transcriptomic differences to determine the molecular mechanism of tumorigenesis with a focus on DNA repair and telomere maintenance pathways in young, low-risk OCSCC. The proposed study and training aims are to develop a career development plan that will be critical to further defining the molecular mechanisms of tumorigenesis through next generation sequencing in young OCSCC patients. In AIM1, we seek to analyze young, low-risk OCSCC patients (cases) and traditional, high- risk patients (control) for epidemiologic risk factors and to perform integrated analysis of germline and somatic variants to further elucidate the genomic impact in OCSCC. We will then use high throughput RNASeq to analyze the transcriptome in these two groups to further characterize differences or similarities and allow greater insight into the potential mechanisms of tumorigenesis. In AIM2 we will investigate the impact of previously identified germline candidate gene mutations in the DNA repair and telomere maintenance pathways on tumorigenesis and genome instability using genetic editing and in vitro techniques. This study will allow us to develop and analyze data critical to understanding of OCSCC and to provide me, the P.I., the opportunity to develop the research tools, fund of knowledge, and skills necessary to perform this type of study as I seek to become an independently funded clinician-scientist. The P.I. is a head and neck surgical oncologist and witnesses the daily impact head and neck cancer has on patients, thus recognizes the need to improve patient care through translational research. The P.I. is an active member of the Head and Neck oncology program, who is strongly supported by his department, as well as a team of strong bio-informatics collaborators with significant experience in making substantial changes to the field of cancer genetics. The P.I. has designed a mentored training and educational program to directly correlate with the research aims to allow an integrated education for advanced sequencing techniques. Based on our joint experience, we expect our research to have high potential for translational application to patient care. In summary, this proposal has significant potential to dramatically impact the lives of patients with OCSCC and will provide substantial training and mentorship for the P.I. to become an independent investigator.